Fabry Disease

NORD gratefully acknowledges R.J. Desnick, PhD, MD, Dean for Genetic and Genomic Medicine, Professor and Chairman Emeritus, and Dana Doheny, MS, Research Coordinator and Genetic Counselor, International Center for Fabry Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, for assistance in the preparation of this report.

Synonyms of Fabry Disease

alpha-galactosidase A deficiency

Anderson-Fabry disease

angiokeratoma corporis diffusum

angiokeratoma diffuse

ceramide trihexosidase deficiency

GLA deficiency

Subdivisions of Fabry Disease

type 1 classic phenotype

type 2 later-onset phenotype

General Discussion

Fabry disease is a rare inherited disorder of lipid (fat) metabolism resulting from the deficient activity of the enzyme, alpha-galactosidase A (a-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders. This enzymatic deficiency is caused by mutations (or alterations) in the a-Gal A gene (abbreviated as GLA) that instructs cells to make the a-Gal A enzyme. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. a-Gal A functions to break down specific complex sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3), lyso-GL-3/Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in the cell abnormalities and organ dysfunction that particularly affect the heart and kidneys.
The GLA gene is located on the X-chromosome and therefore, Fabry disease is inherited as an X-linked disorder. Males are typically more severely affected than females. Females have a more variable course and may be asymptomatic or as severely affected as males (see Genetics section below).
There are two major disease phenotypes: the type 1 “classic” and type 2 “later-onset” subtypes. Both lead to renal failure, and/or cardiac disease, and early death (Desnick 2001). Type 1 males have little or no functional a-Gal A enzymatic activity (<1% of normal mean), and marked accumulation of GL-3/Gb3 and related glycolipids in capillaries and small blood vessels which cause the major symptoms in childhood or adolescence. These include the acroparesthesia (excruciating pain in the hands and feet which occur with exercise, fevers, stress, etc.); angiokeratomas (clusters of red to blue rash-like discolorations on the skin); anhidrosis or hypohidrosis (absent or markedly decreased sweating); gastrointestinal symptoms including abdominal pain and cramping, and frequent bowel movements; and a characteristic corneal dystrophy (star-burst pattern of the cornea seen by slit-lamp ophthalmologic examination) that does not affect vision (Desnick 2001, Desnick 2009, Germain 2010). With increasing age, the systemic GL-3/Gb3 deposition, especially in the heart leads to arrhythmias, left ventricular hypertrophy (LVH) and then hypertrophic cardiomyopathy (HCM), and in the kidneys to progressive insufficiency then to renal failure, and/or to cerebrovascular disease including transient ischemic attacks (TIAs) and strokes. Prior to renal replacement therapy (i.e., dialysis and transplantation) and enzyme replacement therapy (ERT), the average age of death of affected males with the type 1 classic phenotype was ~40 years (Columbo et al. 1967). The incidence of males with the type 1 classic phenotype is about 1 in 40,000 males, but varies with demography and race, ranging from about ~1 in 18,000 to 1 in 95,000 based on newborn screening studies (Liao 2014, Uribe 2013, Mechtler 2012, Whittman 2012, Scott 2013, Inoue 2013, Hwu 2009, Spada 2006).
In contrast, males with the type 2 “later-onset” phenotype (previously called cardiac or renal variants) have residual a-Gal A activity, lack GL-3/Gb3 accumulation in capillaries and small blood vessels, and do not manifest the early manifestations of type 1 males (i.e., the acroparesthesias, hypohidrosis, angiokeratomas, corneal dystrophy, etc). They experience an essentially normal childhood and adolescence. They typically present with renal and/or cardiac disease in the third to seventh decades of life. Most type 2 later-onset patients have been identified by enzyme screening of patients in cardiac, hemodialysis, renal transplant, and stroke clinics (e.g., Linthorst 2010, Elliott 2011, Herrera 2013, Baptista 2014), and recently by newborn screening. Based on these screening studies (e.g., Liao 2014, Uribe 2013, Mechtler 2012, Whittman 2012, Scott 2013, Inoue 2013, Hwu 2009, Spada 2006) the incidence of type 2 later-onset males varies by demography, ethnicity, and race, but is at least 10 times more frequent than that of the type 1 males from the same region, ethnic group, or race.
Clinical manifestations in heterozygous females from families with the type 1 classic phenotype are variable due to random X-chromosomal inactivation (Dobrovolny 2011) and range from asymptomatic to as severe as type 1 classic males (Desnick, 2009, Germain 2015). Type 2 heterozygotes may be asymptomatic or develop renal or cardiac manifestations later in life. At least 90% of type 1 heterozygotes have the characteristic corneal findings, while the type 2 heterozygous females typically lack the characteristic corneal findings or other early type 1 manifestations (Desnick, 2009, 2014). However, the frequency of manifestations in type 2 heterozygotes has not been systematically investigated to date.

Signs & Symptoms

Type 1 Classic Phenotype

The signs and symptoms of males with type 1 classic phenotype typically begin in childhood or adolescence. Symptoms increase with age due to the progressive glycolipid accumulation in the vascular system, kidneys, and heart leading to kidney failure, heart disease, and/or strokes. Early and progressive clinical symptoms include:

Acroparesthesias. Pain is an early symptom of the Classic subtype and may occur as early as 2-8 years old in males and during childhood or adolescence in female heterozygotes. Affected individuals may experience episodes of severe burning pain in the hands and the feet (acroparesthesia). Severe episodes of pain (Fabry’s crises) may last for hours to days and are frequently triggered by exercise, fatigue, stress, and/or fever.

Anhidrosis or hypohidrosis. Type 1 males and some type 1 females have decreased or absent sweat production (hypohidrosis or anhidrosis) and discomfort (heat intolerance) in warm temperatures, with exercise, or fevers.

Angiokeratomas. Early symptoms also include the appearance of a reddish to dark-blue skin rash, especially in the area between the hips and the knees. These skin lesions may be flat or raised. They often are found in the umbilical area or genitals of type 1 males. Typically, males and females with the type 2 later-onset phenotype do not have these characteristic skin lesions.

Gastrointestinal problems. Abdominal cramping, frequent bowel movements, and diarrhea may also occur, particularly after a large meal.

Corneal dystrophy. Patients with the type 1 Classic subtype have abnormal deposits of glycolipids in their corneas resulting in a characteristic change which can be seen by an experienced ophthalmologist. These changes do not affect vision. Blood vessels in the eyes may appear twisted (cork screw-like; contorted) and/or slightly enlarged (dilated) due to the glycolipid accumulation in the vessel walls.

Additional Type 1 symptoms. Other symptoms that may be associated with Fabry disease include chronic fatigue, dizziness, headache, generalized weakness, nausea, and/or vomiting, delayed puberty, lack of or sparse hair growth, and rarely malformation of the joints of the fingers. Some type 1 classic males have abnormal accumulation of lymph in the feet and legs associated with swelling (lymphedema). In these cases, lymph, a body fluid containing certain white blood cells, fats, and proteins, accumulates outside blood vessels in spaces between cells and drains or flows back into the bloodstream via lymph vessels. Lymphedema results from disruption of lymph’s normal drainage due to the glycolipid accumulation in the lymphatic vessels and lymph nodes.

Common Manifestations in Type 1 and 2 Males:

With advancing age in type 1 males, typically in the third to fourth decades, and in type 2 males in the third to sixth decades, the progressive GL-3/Gb3 glycolipid deposition leads to renal and heart manifestations as described below. Many of the type 2 later-onset males who lack the early manifestations in the type 1 boys, are detected in renal, heart, or stroke clinics. Patients with the type 2 later-onset subtype typically do not have the skin lesions (angiokeratoma), sweat normally, do not experience the Fabry pain or crises, and do not have heat intolerance or corneal involvement. These individuals develop heart or kidney disease later in adult life.

Signs of progressive organ involvement include:

Renal dysfunction. Progressive decrease in renal function is due to the progressive accumulation of GL-3/Gb3 in the kidneys. There is histological evidence of this accumulation and ensuing cellular and vascular injury to renal tissue beginning in childhood and adolescence (Tondel 2008, Najafian 2013, Wijburg 2015.) in type 1 classic males and females. In the type 1 classic males the decline in kidney function progresses to kidney failure and the need for dialysis or transplantation typically by 35 to 45 years of age. In type 2 males, kidney involvement typically occurs in the fourth decade and later. Kidney involvement in type 1 female heterozygotes is more variable. Only about 10-15% of type 1 females develop kidney failure. It is not clear what percentage of type 2 females develop renal dysfunction, if any.

Cardiac disease. GL-3/Gb3 deposition can be found in all cardiac tissues, including myocytes, nerves, and coronary arteries. Heart disease includes heart enlargement, typically left ventricular hypertrophy (LVH) leading to hypertrophic cardiomyopathy (HCM), rhythm abnormalities (arrhythmias), and heart failure. LVH occurs in about 20% of males and females with an average age of diagnosis in the early 40s among males and late 40s among females. Early heart involvement in type 1 males typically includes arrhythmias and mitial insufficiency in their twenties followed by LVH leading to HCM. Type 2 later-onset males develop the same heart manifestations as type 1 males and may be first diagnosed in cardiac clinics among patients with LVH or HCM. Heterozygous females with the type 1 phenotype often have sinus bradycardia as an early finding leading to LVH and HCM. It is not clear if type 2 heterozygotes develop heart disease or if they have additionally autosomal dominant HCM due to sarcomere mutations (Desnick, et al., 2014).

Cerebrovascular complications. As a result of the progressive GL-3/Gb3 deposition in the small blood vessels in the brain, about 7% of males and 4% of females with Fabry disease, particularly those with the type 1 phenotype, experience ischemic or hemorrhagic strokes, occurring typically in the fourth decade of life or later (Wilcox 2008).

Causes

Genetics:

Fabry disease is caused by mutations (alterations) in the alpha-galactosidase A (GLA) gene located on the X-chromosome. Chromosomes are found in the nucleus of all cells. They carry the genetic characteristics of each individual in thousands of specific segments, called “genes”, that span the length of the chromosomes. Each of these genes has a specific function in the body. Human chromosomes are organized in pairs, numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Individuals inherit one chromosome in each pair from each parent. Therefore, in X-linked disorders including Fabry disease, disease traits on the X chromosome can be masked in females by the normal gene on the other X chromosome. More specifically, because only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially “turned off”, usually in a random pattern (random X chromosome inactivation). This means that in X-linked disorders some cells will have the X chromosome with the mutated gene activated and some will have the X chromosome with the functioning gene activated. Therefore, in Fabry disease the symptoms and severity of organ involvement are dependent on what tissues/organs have the X chromosome with the GLA gene mutation activated, which partially explains why the disease severity in females is more variable than in their affected male relatives. Since males have only one X chromosome, if a male has the X chromosome with the GLA gene mutation, he will be affected with the disorder. Therefore, males with Fabry disease are more uniformly affected, whereas females, due to random X-inactivation, may be asymptomatic or as severely affected as males.

Males with X-linked Fabry disease transmit the GLA gene mutation to all their daughters, who are heterozygotes, but never to their sons. Female heterozygotes have a 50 percent risk of transmitting the disease to each of their children, both daughters and sons, with each pregnancy.

The GLA gene normally instructs the body’s cells to make the α-Gal A enzyme, which breaks down globotriaocylceramide (GL-3/Gb3) in the cell’s lysosomes. Fabry disease is caused by mutations in the GLA gene. There are over 770 mutations in the GLA gene that are responsible for Fabry disease, causing the Type 1 or 2 phenotypes. Thus, the severity and range of symptoms may vary among individuals depending on the GLA mutation in their family. Some mutations markedly alter the enzyme such that it has little to no activity. These mutations cause the type 1 Classic subtype, while other mutations result in a small amount of residual enzyme activity and the type 2 later-onset subtype. The signs and symptoms of Fabry disease develop due to deficient or low activity of α-Gal A. Patients with the type 1 classic phenotype, who have no or very low activity levels (less than 1% of normal), accumulate the GL-3/Gb-3 glycolipid substance (and related glycolipids) in most tissues of the body, especially small blood vessels, and certain cells in the heart and kidneys. Patients with the type 2 later-onset phenotype have residual enzyme activity (1-10% of normal), and also accumulate GL-3/Gb3, but to a lesser extent and at a slower rate. They tend to have a somewhat less severe form of the disease, but males with the type 2 subtype ultimately develop severe cardiac disease and/or renal failure.

Affected Populations

Fabry disease is a rare pan ethnic disorder, meaning that it occurs in all racial and ethnic populations affecting males and females. It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males. The type 2 later-onset phenotype is more frequent, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males.

Related Disorders

Symptoms of the following disorders can be similar to those of Fabry disease. Comparisons may be useful for a differential diagnosis:

Schindler disease is a rare inherited metabolic disorder characterized by a deficiency of the lysosomal enzyme alpha-N-acetylgalactosaminidase (alpha-NAGA), which leads to an abnormal accumulation of certain complex compounds (glycosphingolipids and oligosaccharides) in many tissues of the body. Schindler disease is inherited as an autosomal recessive disorder. There are three types of Schindler disease. The classical form of the disorder, known as Schindler disease, type I, has an infantile onset. Affected individuals appear to develop normally until approximately one year of age, when they begin to lose previously acquired skills that require the coordination of physical and mental activities (developmental regression). Additional neurological and neuromuscular symptoms may become apparent, including diminished muscle tone (hypotonia) and weakness; involuntary, rapid eye movements (nystagmus); visual impairment; and episodes of uncontrolled electrical activity in the brain (seizures). With continuing disease progression, affected children typically develop restricted movements of certain muscles due to progressively increased muscle rigidity, severe intellectual disability, hearing and visual impairment, and a lack of response to stimuli in the environment. Type 2 Schindler disease also known as Kanzaki disease, is the adult-onset form with symptoms presenting in the second or third decade of life. The disorder is characterized by angiokeratoma, a skin lesion and distribution similar to that seen in type 1 classic Fabry disease. Presentation may also include lymphedema, intellectual impairment, and distinct facial features including mildly coarse features, thick lips, a depressed nasal bridge and an enlarged tip of the nose. Type III Schindler disease is an intermediate form the disorder. Symptoms can range from more serious intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays and mild autism-like symptoms. (For more information on this disorder, choose “Schindler” as your search term in the Rare Disease Database.)

Gaucher disease is one of the most common of the lipid storage diseases and is characterized by the abnormal accumulation of certain fatty substances in various organs of the body. Symptoms develop due to a deficiency in the enzyme glucocerebrosidase and may include enlargement of the liver (hepatomegaly) and spleen (splenomegaly), a general feeling of ill health (malaise), visual difficulties, abdominal swelling, severe bone pain and bone disease. Gaucher disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Gaucher” as your search term in the Rare Disease Database.)

Fucosidosis is an extremely rare inherited lysosomal storage disease characterized by a deficiency of the enzyme alpha-L-fucosidase. There are at least two types of fucosidosis (i.e., type 1 and type 2), determined mainly by the severity of the enzyme deficiency and resulting symptoms. The symptoms of fucosidosis type 1, the most severe form of the disease, may become apparent as early as six months of age. Symptoms may include a skin lesion similar to Fabry disease (angiokeratoma), progressive deterioration of the brain and spinal cord (central nervous system), intellectual disability, loss of previously acquired intellectual skills, and growth retardation leading to short stature. Other physical findings and features become apparent over time, including multiple deformities of the bones (dysostosis multiplex), coarse facial features, enlargement of the heart (cardiomegaly), enlargement of the liver and spleen (hepatosplenomegaly), and/or episodes of uncontrolled electrical activity in the brain (seizures). Additional symptoms may include increased or decreased perspiration and/or malfunction of the gallbladder and/or salivary glands. Fucosidosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “fucosidosis” as your search term in the Rare Disease Database.)

Erythromelalgia is a rare condition that primarily affects the feet and, less commonly, the hands. It is characterized by intense burning pain of affected extremities, severe redness, and increased skin temperature that may be episodic or almost continuous in nature.

Diagnosis

The diagnosis of Fabry disease is frequently made by physicians who recognize the pain in the extremities, absent or decreased sweating (anhidrosis or hypohidrosis), typical skin lesions (angiokeratoma), gastrointestinal abnormalities, corneal involvement, renal insufficiency, and heart symptoms present in childhood, adolescence or adulthood. The diagnosis is confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in males and females.

Prenatal diagnosis of Fabry disease is made by measuring a-Gal A activity and demonstrating the family-specific GLA mutation in cells that are removed from the amniotic fluid surrounding the developing fetus at about 15 weeks of pregnancy. Early prenatal diagnosis at about 10 weeks of pregnancy can be made by a-Gal A enzyme and gene analyses of villi obtained by chronic villus sampling.

Standard Therapies

Treatment

The U.S. Food and Drug Administration (FDA) approved an enzyme replacement therapy called agalsidase beta (Fabrazyme®) as a treatment for patients with Fabry disease in 2003. Fabrazyme®, which is administered intravenously, is a form of the human enzyme produced by recombinant DNA technology. This replacement of the missing enzyme reduces the accumulation of the accumulated glycolipids in cells, including the cells of the kidney and other organs. Double-blind, placebo-controlled Phase 3 and 4 clinical trials have demonstrated the safety and effectiveness of Fabrazyme® enzyme replacement therapy for Fabry disease.

Fabrazyme® had been designated an orphan drug and was approved by the FDA under an accelerated or early approval mechanism. One of the requirements of the accelerated approval is that the sponsor complete a post-market study verifying that patients will benefit from the product, which was accomplished and reported in 2007.

For additional information on Fabrazyme®, contact the manufacturer:

Genzyme Corporation

One Kendall Square

Cambridge, MA, 02139

Tel: (617) 252-7500

Fax: (617) 252-7600

Low doses of diphenylhydantoin, carbamazepine, or neurontin, may help to prevent the acroparesthesias- the discomfort in the hands and feet. Other later complications (e.g., kidney failure or heart problems) should be treated symptomatically after consultation with a physician who is experienced in the care of people with Fabry disease. Hemodialysis and kidney (renal) transplantation may be necessary in cases that have progressed to kidney failure.

Genetic counseling will be of benefit for affected individuals and their families. Other treatment is supportive.

Investigational Therapies

The FDA has granted orphan drug status to AT1001, manufactured by Amicus Therapeutics, Inc., for the treatment of Fabry disease. This oral therapy was designed to enhance an individual’s residual alpha-galactosidase A activity. Studies are being conducted to determine its safety and effectiveness. For information, contact:

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials sponsored by private sources, contact:

Feldt-Rasmussen U, et al. Diagnostic Dilemma: A Young Woman with Fabry Disease Symptoms, No Family History, and a “Sequencing Cryptic” a-Galactosidase A Large Deletion. Mol. Genet Metab. 2011;104:314-318.

Years Published

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